Peptide derivatives

ABSTRACT

The present invention relates to the peptides consisting of 25-50 amino acid residues and comprising the following peptide sequence: 
     
         Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His 
    
     -His-Leu-Ile-Ala-Glu-Ile                                   (I) 
     and amides and salts thereof. The peptides have stronger inhibitory activity against hPTH when compared with conventional inhibitors, and therefore, they are expected to be useful for the treatment of various diseases associated with calcium or phosphoric acid metabolism such as hypercalcemia and osteoporosis, or diseases associated with PTH and PTHrP.

FIELD OF ART

The present invention relates to novel peptide derivatives. In more particular, it relates to parathyroid hormone antagonists.

BACKGROUND OF THE INVENTION

Parathyroid hormone (referred to as PTH hereinafter) is a peptide hormone consisting of 84 amino acid residues, which is responsible for bone and calcium metabolism. A peptide fragment consisting of the first to 34th amino acid residues at the N-terminal of PTH, which is called PTH (1-34), has the same biological activity as PTH. On the other hand, other peptide fragments which lack the first few N-terminal amino acid residues, PTH (3-34), PTH (7-34), and the like, are known to suppress PTH activity.

Recently, it has been found that a PTH-related peptide (referred to as PTHrP hereinafter) derived from human carcinoma exhibits biological activity similar to PTH, and its chemical structure has been determined (Suva et al, Science, Vol.237, 893, 1987). The human PTHrP is a polypeptide consisting of 141 amino acid residues. It has biological activity similar to that of PTH, such as elevation of blood calcium level, acceleration of born absorption, lowering of blood phosphorous level, lowering of urinary calcium level, increasing of urinary cAMP level, and activation of hydroxylase at the 1-position of vitamin D in kidney (Horiuchi et al, Science, Vol.238, 1988; Kemp et al, Science, Vol.238, 1988).

Primary structure of PTHrP has poor similarity to that of PTH although partial structure of PTHrP at the amino terminal shows similarity to that of PTH. In spite of the fact, fragments of PTHrP, which lack a few amino terminal residues, such as PTHrP (3-34), suppress PTH activity likewise in PTH (Rabbani et al, oral speech at the meeting of the America Bone Metablism Association, 1988).

PTH derivatives such as [Tyr³⁴ ]-hPTH (3-34)-NH₂ and PTHrP derivatives such as hPTHrP (3-34)-NH₂ are known as a PTH antagonist. However, there has been a need to discover move potent PTH antagonist activity. The present invention relates to the peptides consisting of 25-50 amino acid residues and comprising the following peptide sequence, and amides and salts thereof.

    Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile (Seq Id No. 1)                    (I)

The following abbreviations are used in this text.

Asp: aspartic acid

Thr: threonine

Ser: serine

Asn: asparagine

Gln: glutamine

Glu: glutamic acid

Gly: glycine

Ala: alanine

Met: methionine

Ile: isoleucine

Leu: leucine

Phe: phenylalanine

Lys: lysine

His: histidine

Arg: arginine

Boc: t-butoxycarbonyl

Z: benzyloxycarbonyl

OcHx: cyclohexyl ester

OBzl: benzyl ester

Bzl: benzyl

Tos: p-toluenesulfonyl

Cl-Z: 2-chlorobenzyloxycarbonyl

The peptide derivatives of the present invention contain at least the peptide sequence represented by the formula (I) mentioned above. For instance, the peptide derivatives of the invention may be represented by the following formula (II):

    X-Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-Y-z                             (II)

wherein X represents H, (Seq. ID Nos: 2-5), H-Gln (Seq. ID Nos: 6-9), H-A-Gln, (Seq. ID Nos. 6-9) H-Glu-A-Gln- (Seq. Id. Nos: 14-17), or Ser-Glu-A-Gln- (Seq. ID Nos: 18-21), wherein A is Ile, Thr, Val, or Leu; Y represents His-Thr-Ala, His-Thr-Ala-Glu-Ile-Arg-Ala, His-Thr-Ala-Glu-Ile-Arg-Ala-Thr-Ser-Glu-Val, His-Thr-Ala-Glue-Ile-Arg-Ala-Thr-Ser-Glu-Val-Ser-Pro-Asn-Ser-Lys-Pro-Asn; Z represents OH or NH₂.

The following Table 1 lists specific examples of the peptide derivatives of the invention.

                                      TABLE 1                                      __________________________________________________________________________     X--Leu--Met--His--Asn--Leu--Gly--Lys--Ser--Ile--Gln--Asp--Leu--Arg--Arg--      Arg--Phe--Phe--Leu--His--His--Leu--Ile--Ala--Glu--Ile--Y--Z                    Compound                                                                       No.   X            Y           Z                                               __________________________________________________________________________     1     H--Ser--Glu--Ile--Gln                                                                       His--Thr--Ala                                                                              NH.sub.2                                                                          (SEQ ID NO: 18)                              2     H--Glu--Ile--Gln                                                                            His--Thr--Ala                                                                              NH.sub.2                                                                          (SEQ ID NO: 14)                              3     H--Ile--Gln  His--Thr--Ala                                                                              NH.sub.2                                                                          (SEQ ID NO: 10)                              4     H--Gln       His--Thr--Ala                                                                              NH.sub.2                                                                          (SEQ ID NO: 6)                               5     H            His--Thr--Ala                                                                              NH.sub.2                                                                          (SEQ ID NO: 2)                               6     H--Ser--Glu--Ile--Gln                                                                       His--Thr--Ala                                                                              OH (SEQ ID NO: 18)                              7     H--Ser--Glu--Ile--Gln                                                                       His--Thr--Ala--Glu--                                                                       NH.sub.2                                                                          (SEQ ID NO: 19)                                                 Ile--Arg--Ala                                               8     H--Ser--Glu--Ile--Gln                                                                       His--Thr--Ala--Glu--                                                                       NH.sub.2                                                                          (SEQ ID NO:20)                                                  Ile--Arg--Ala--Thr--                                                           Ser--Glu--Val                                               9     H--Ser--Glu--Ile--Gln                                                                       His--Thr--Ala--Glu--                                                                       NH.sub.2                                                                          (SEQ ID NO: 21)                                                 Ile--Arg--Ala--Thr--                                                           Ser--Glu--Val--Ser--                                                           Pro--Asn--Ser--Lys--                                                           Pro--Asn                                                    10    H--Ser--Glu--Val--Gln                                                                       His--Thr--Ala                                                                              NH.sub.2                                                                          (SEQ ID NO: 18)                              11    H--Ser--Glu--Thr--Gln                                                                       His--Thr--Ala                                                                              NH.sub.2                                                                          (SEQ ID NO: 18)                              12    H--Ser--Glu--Leu--Gln                                                                       His--Thr--Ala                                                                              NH.sub.2                                                                          (SEQ ID NO: 18)                              __________________________________________________________________________

The peptide derivatives of the invention may be used after conversion to pharmacologically acceptable salts thereof, such as hydrochloride or acetate.

The PTHrP derivatives of the invention represented by the formula (I) or (II) may be prepared by repeating condensation reaction between relevant protected amino acids by means of conventional solid phase method, said reaction being sequentially conducted starting from C-terminal and according to the amino acid sequence shown in formula (I) or (II), and removing the protective groups and carrier to which the C-terminal amino acid residue has been linked by known methods such as acid decomposition and aminolysis. The peptide synthetic method mentioned above and the starting amino acid derivatives used therein are described in detail in various text books (See Izumiya et al, "Basis and Practice of Peptide Synthesis", published by Maruzen, 1985; Gross and Meienhofer's, "The Peptides", Vol.2, Academic Press, 1980).

The solid phase carriers used in the peptide synthesis for preparing the peptide derivatives of the present invnetion may be conventional ones, and specific examples are polystyrene resins of substituted benzyl type, polystyrene resins of hydroxymethylphenylacetic amide type, substituted benzhydrylpolystyrene resins or polyacrylamide resins having a functional group for binding to a peptide. Amino acids condensation may be also conventional, and dicyclohexylcarbodiimide (DDC), acid anhydride, and activated ester methods may be used.

Protective groups in the starting protected amino acids may be groups which are known in conventional peptide synthesis and easily removed by conventional means such as acid decomposition, reduction or aminolysis. Specific examples of amino protective group are formyl; trifluoroacetyl; benzyloxycarbonyl; substituted benzyloxycarbonyls such as (ortho- or para-) chlorobenzyloxycarbonyl, and (ortho- or para-) bromobenzyloxycarbonyl; and aliphatic oxycarbonyl such as t-butoxycarbonyl and t-amyloxycarbonyl. Carboxylic acid in amino acids may be protected by being converted to ester group. As the ester group, there may be mentioned benzyl ester; substituted benzyl ester such as methoxybenzyl ester; alkyl esters such as cyclohexyl ester, cycloheptyl ester, or t-butyl ester. Guanidino group does not require any protective group, but may be protected by nitro; or arylsulfonyl such as tosyl, methoxybenzenesulfonyl, or mesithylenesulfonyl. Protecting groups for imidazole include tosyl, benzyl, and dinitrophenyl. Hydroxy groups present in serine and threonine molecules may be non-protected or protected by benzyl or substituted benzyl. The indole group in tryptophan molecule may be non-protected or protected by formyl or the like.

The final deprotection and detachment of a resultant peptide from the carrier may be conducted by the action of anhydrous hydrogen floride in the presence of one of various scavengers. Examples of the scavengers are anisole, (ortho-, metha-, or para-) cresol, dimethylsulfide, thiocresol, ethanediol, and mercaptopyridine, which are all conventional in peptide synthesis. Purification of the resultant peptide may be conducted by means of conventional methods, such as gel-filtration, ion-exchange chromatography, and high- or low-pressure reverse phase chromatography. The peptide thus purified may be converted to its salt by the use of gel-chromatography equilibrated with aqueous acetic acid or aqueous hydrochloric acid.

BEST MODE FOR PRACTICING THE INVENTION

The following examples are presented by way of illustration of certain specific embodiments of the invention. The examples are representative only and should not be construed as limiting in any respect.

EXAMPLE 1

Synthesis of Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-His-Thr-Ala-NH₂ (compound 1 in Table 1)

The tile peptide was synthesized by routine solid phase method. As the solid phase carrier, 1% cross-linked 4-methylbenzylhydrylamine polystyrene (amino group content: 0.5 mmol) was used. Amino acid derivatives used for the peptide synthesis were;

Box-Ala, Boc-Asp(OcHx), Boc-Asn, Boc-Arg(Tos), Boc-Gly, Boc-Glu(OcHx), Boc-Gln, Boc-His(Tos), Boc-Ile, Boc-Leu, Boc-Lys(Cl-Z), Boc-Met, Boc-Phe, Boc-Ser(Bzl), Boc-Thr(Bzl), Boc-Val

The elongation of peptide chain was performed by repeating the steps described in Table 2.

                  TABLE 2                                                          ______________________________________                                                             number of  Time                                            Treatment           repeats    (min)                                           ______________________________________                                         Deprotection [Treatment 1]                                                     1. washing with dichloromethane                                                                    1          1.0                                             2. washing with 50% trifluoroacetic                                                                1          5.0                                             acid/dichloromethane                                                           3. deprotection with 50% trifluoro-                                                                1          25                                              acetic acid/dichloromethane                                                    4. washing with dichloromethane                                                                    1          1.0                                             Neutralization [Treatment 2]                                                   1. 10% diisopropylethylamine                                                                       2          2.0                                             /dichloromethane                                                               2. washing with dichloromethane                                                                    2          5.0                                             3. washing with dimethylformamide                                                                  5          1.0                                             Condensation* [Treatment 3]                                                    1. symmetric acid anhydride of                                                                     1          1.0                                             tert-butoxycarbonylamino acid                                                  (2-equivalents)**/dimetylformamide                                             2. washing with dimethylformamide                                                                  5          1.0                                             3. washing with dichloromethane                                                                    5          1.0                                             ______________________________________                                    

The carrier and protective groups were removed according to known HF method. In detail, protected peptide-polystyrene was incubated in 10% para-cresol, 65% dimetyl sulfide, and 25% anhydrous hydrogen fluoride (20 ml) at 0° C. for 2 hours, and then the reaction mixture was evaporated to remove the solvent under reduced pressure and treated with 5% para-cresol and 95% anhydrous hydrogen fluoride at 0° C. for 1 hour. After evaporation of the reaction mixure under reduced pressure, the residue was washed with ethyl acetate, extracted with 1M acetic acid, and lyophilized to obtain crude peptide. The crude peptide was applied to reverse phase high pressure chromatography, and eluted with linear gradient of water-acetonitrile containing 0.1% trifluoroacetic acid. After lyophilization, the material was applied to CM Toyopearl 650S (1.5×30 cm) in 10 mM ammonium acetate (pH6.0), and separated and purified with linear gradient of 20 mM-1.0M sodium acetate. The fraction containg desired compound was gel filtrated through Sephadex G25 (15×50 cm) preequilibrated with 2% acetic acid, and then lyophilized, and converted to the acetate by gel filtration previously described to obtain the pure title compound.

Yield:31 mg

Amino acid analysis : Degraded materials obtained by hydrolysis in 5.5M hydrochloric acid at 110° C. for 48 hours were analized in an amino acid analizer. Theoretical values are shown in parenthesis. Correction on degradation of amino acids during the hydrolysis was not done.

Asp 1.93(2), Thr 0.96(1), Ser 1.56(2), Glue 4.07(4) Gly 0.94(1), Ala 2.01(2), Met 0.91(1), Ile 3.84(4) Leu 5.19(5), Phe 1.94(2), Lys 0.95(1), His 3.85(4) Arg 3.13(3)

Optical ratation [α]²⁵ _(D) : -66° (C=0.24, 1M acetic acid)

EXAMPLE 2

Synthesis of Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-His-Thr-Ala-NH₂ (compound 3 in Table 1).

The title peptide was synthesized by the method as described in Example 1.

Optical raotation [α]²⁵ _(D) :-65° (C=0.1, 1M acetic acid)

EXAMPLE 3

Synthesis of Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-His-Thr-Ala-NHz (compound 5 in Table 1).

The title peptide was synthesized by the method as described in Example 1.

Optical ratation [α]²⁵ _(D) :-62° (C=0.1, 1M acetic acid)

EXAMPLE 4

Synthesis of Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-His-Thr-Ala-Glu-Ile-Arg-Ala-NH.sub.2 (compund 7 in Table 1).

The title peptide was synthesized by the method as described in Example 1.

Optical ratation [α]²⁵ _(D) : -95° (C=0.13, 1M acetic acid)

EXPERIMENT Determination of PTH antagonism Method

PTH antagonism of the peptide derivatives of the invention was determined on the basis of cAMP production using cultured osteoblast MC3T3-El derived from mice.

The cultured cells were plated on 12 well multiwellculture plate at a ratio of 1×10⁵ cells/well. Using α-modified MEM containing 10% quassifetal bovine serum as a culture medium, the cells were cultured at 37° C. under 95% air-5% CO₂ for 3 days. The medium was exchanged by α-modified MEM containing 1% bovine serum albumin and incubated for 6 hours. The medium was again exchanged by α-modified MEM containing the peptide derivative in various concentrations, 5×10⁻⁹ M hPTH (1-34), 1% bovine serum albumin, and 1 mM isobutyl methylxanthine, and further incubated.

After one hour incubation, the medium and the cells were separated. The separated medium was used as a test sample for determination of cAMP without further treatment. The separated cells was treated with 90% n-propyl alcohol to extract cAMP according to Yamaguchi et al method (Journal of Biological Chemistry, Vol.262, 7711-7718, 1987). cAMP determination was conducted using a cAMP-radioimmunoassay kit which is commercially available. Table 3 shows 50% inhibition of cAMP production caused by the peptide derivatives of the invention when the amount of cAMP produced by 5×10⁻⁹ M hPTH (1-34) is defined as 100%. As a control, [Tyr³⁴ ]-hPTH (3-34)-NH₂ and hPTHrP (3-34)-NH₂, which are known as a PTH antagonist, were employed.

                  TABLE 3                                                          ______________________________________                                         Compound No.            IC.sub.50                                              ______________________________________                                         Compound 1              0.007                                                  Compound 2              0.008                                                  Compound 3              0.015                                                  Compound 4              0.476                                                  [Tyr.sup.34 ]- hpTH (3-34) - NH.sub.2                                                                  1                                                      hpTHrp (3-34) - NH.sub.2                                                                               0.087                                                  ______________________________________                                    

Results

Table 3 shows that the compounds of the present invention exhibit 50% inhibition at a concentration of 1/140 as compared with that of [Tyr³⁴ ]-hPTH (3-34)-NH₂, and at a concentraiton of 1/12 as compared with hPTHrP (3-34)-NH₂.

Industrial utility

The peptide derivatives of the present invention have stronger inhibitory activity against hPTH when compared with conventional inhibitors, and therefore, they are expected to be useful for the treatment of various diseases associated with calcium or phosphoric acid metabolism such as hypercalcemia and osteoporosis, or diseases associated with PTH and PTHrP.

    __________________________________________________________________________     SEQUENCE LISTING                                                               (1) GENERAL INFORMATION:                                                       (iii) NUMBER OF SEQUENCES: 21                                                  (2) INFORMATION FOR SEQ ID NO:1:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 25 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                                (v) FRAGMENT TYPE:                                                            (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY:                                                                  (B) LOCATION:                                                                  (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION:                                                         (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   ( B) TITLE:                                                                    (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                        LeuMetHisAsnLeuGlyLy sSerIleGlnAspLeuArgArgArg                                 151015                                                                         PhePheLeuHisHisLeuIleAlaGluIle                                                 2025                                                                           (2) INFORMATION FOR SEQ ID NO:2:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 28 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                   (A) NAME/KEY: modified-site                                                   (B) LOCATION: 28                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ala-OH or                                        Ala-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                      (G) DATE:                                                                     (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                        LeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArgArgArg                                  1510 15                                                                        PhePheLeuHisHisLeuIleAlaGluIleHisThrXaa                                        2025                                                                           (2) INFORMATION FOR SEQ ID NO:3:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 32 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 32                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ala-OH or                                         Ala-NH2"                                                                      (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                           (K) RELEVANT RESIDUES IN SEQ ID NO:                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                        LeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArgArgArg                                  151015                                                                         PhePheLeuHisHisLeuIleAlaGluIleHisThrAl aGluIle                                 202530                                                                         ArgXaa                                                                         (2) INFORMATION FOR SEQ ID NO:4:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 36 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                                (v) FRAGMENT TYPE:                                                            (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 36                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Val-OH or                                        Val-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                    (B) TITLE:                                                                    (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                        LeuMetHisAsn LeuGlyLysSerIleGlnAspLeuArgArgArg                                 151015                                                                         PhePheLeuHisHisLeuIleAlaGluIleHisThrAlaGluIle                                  2025 30                                                                        ArgAlaThrSerGluXaa                                                             35                                                                             (2) INFORMATION FOR SEQ ID NO:5:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 43 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                           (A) ORGANISM:                                                                 (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (v iii) POSITION IN GENOME:                                                    (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 43                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Asn-OH or                                        Asn-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                    (B) TITLE:                                                                    (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                        LeuMetHisAsnLeuGlyL ysSerIleGlnAspLeuArgArgArg                                 151015                                                                         PhePheLeuHisHisLeuIleAlaGluIleHisThrAlaGluIle                                  202530                                                                         ArgAlaThrSerGluValSerProAsnSerLysProXaa                                        3540                                                                           (2) INFORMATION FOR SEQ ID NO:6:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 29 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 29                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ala-OH or                                        Ala-NH2"                                                                        (x) PUBLICATION INFORMATION:                                                  (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                       GlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArgArg                                  151015                                                                         ArgPhePheLeuHisHisLeuIleAlaGluIleHisThrXaa                                     20 25                                                                          (2) INFORMATION FOR SEQ ID NO:7:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 33 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                   (B) STRAIN:                                                                   (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                         (B) MAP POSITION:                                                             (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 33                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ala-OH or                                        Ala-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                    (D) VOLUME:                                                                   (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                        GlnLeuMetHisAsnLeuGlyLysSerIleGlnAspL euArgArg                                 151015                                                                         ArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAlaGlu                                  202530                                                                         IleArgXaa                                                                      (2) INFORMATION FOR SEQ ID NO:8:                                               (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 37 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                         (D) DEVELOPMENTAL STAGE:                                                      (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                               (C) UNITS:                                                                    (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 37                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Val-OH or                                        Val-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    ( E) ISSUE:                                                                    (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                        GlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArgArg                                  1 51015                                                                        ArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAlaGlu                                  202530                                                                         IleArgAlaThrSerGluXaa                                                          35                                                                             (2) INFORMATION FOR SEQ ID NO:9:                                                (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 44 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                         (D) DEVELOPMENTAL STAGE:                                                      (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C ) UNITS:                                                                    (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 44                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Asn-OH or                                        Asn-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                      (F) PAGES:                                                                    (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                        GlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArgArg                                  15 1015                                                                        ArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAlaGlu                                  202530                                                                         IleArgAlaThrSerGluValSerProAsnSerLysPro Xaa                                    3540                                                                           (2) INFORMATION FOR SEQ ID NO:10:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 30 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                           (A) ORGANISM:                                                                 (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                      (A) CHROMOSOME/SEGMENT:                                                       (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 1                                                                (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                 Leu"                                                                           (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 30                                                                (C) IDENTIFICATION METHOD:                                                    (D) OTHER INFORMATION: /note="Ala-OH or                                        Ala-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                            (I) FILING DATE:                                                              (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                       XaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArg                                  151015                                                                         ArgArgP hePheLeuHisHisLeuIleAlaGluIleHisThrXaa                                 202530                                                                         (2) INFORMATION FOR SEQ ID NO:11:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 34 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (i i) MOLECULE TYPE:                                                           (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 ( I) ORGANELLE:                                                                (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 1                                                                (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                  Leu"                                                                          (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 34                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ala-OH or                                        Ala-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                     (E) ISSUE:                                                                    (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                       XaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArg                                  1 51015                                                                        ArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAla                                  202530                                                                         GluIleArgXaa                                                                   (2) INFORMATION FOR SEQ ID NO:12:                                              (i ) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 38 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        ( D) DEVELOPMENTAL STAGE:                                                      (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                      (ix) FEATURE:                                                                 (A) NAME/KEY: modified-site                                                    (B) LOCATION: 1                                                                (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                 Leu"                                                                           (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 38                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Val-OH or                                         Val-NH2"                                                                      (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                       XaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArg                                  151015                                                                         ArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAla                                  202530                                                                         GluIleArgAlaThrSerGluXaa                                                       35                                                                             (2) INFORMATION FOR SEQ ID NO:13:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 45 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (i ii) HYPOTHETICAL:                                                           (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vi i) IMMEDIATE SOURCE:                                                       (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 1                                                                (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                  Leu"                                                                          (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 45                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Asn-OH or                                        Asn-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                       XaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArg                                  1 51015                                                                        ArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAla                                  202530                                                                         GluIleArgAlaThrSerGluValSerProAsnSerL ysProXaa                                 354045                                                                         (2) INFORMATION FOR SEQ ID NO:14:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 31 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                    (B) CLONE:                                                                    (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 2                                                                (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                 Leu"                                                                           (ix) FEATURE:                                                                   (A) NAME/KEY: modified-site                                                   (B) LOCATION: 31                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ala-OH or                                        Ala-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                      (G) DATE:                                                                     (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                       GluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeu                                  1510 15                                                                        ArgArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThr                                  202530                                                                         Xaa                                                                            (2) INFORMATION FOR SEQ ID NO:15:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 35 amino acid residues                                             (B) TYPE: amino acid                                                            (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 2                                                                 (C) IDENTIFICATION METHOD:                                                    (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                 Leu"                                                                           (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 35                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ala-OH or                                        Ala-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                      (C) JOURNAL:                                                                  (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                       GluXaaGlnLeuMetHisAsnLeuG lyLysSerIleGlnAspLeu                                 151015                                                                         ArgArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThr                                  202530                                                                         AlaG luIleArgXaa                                                               35                                                                             (2) INFORMATION FOR SEQ ID NO:16:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 39 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                   (B) STRAIN:                                                                   (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A ) CHROMOSOME/SEGMENT:                                                       (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 2                                                                (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                 Leu"                                                                           (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 39                                                               (C ) IDENTIFICATION METHOD:                                                    (D) OTHER INFORMATION: /note="Val-OH or                                        Val-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                       GluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeu                                  151015                                                                         ArgArgArgPhePhe LeuHisHisLeuIleAlaGluIleHisThr                                 202530                                                                         AlaGluIleArgAlaThrSerGluXaa                                                    35                                                                             (2) INFORMATION FOR SEQ ID NO:17:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 46 amino acid residues                                             (B) TYPE: amino acid                                                            (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 2                                                                 (C) IDENTIFICATION METHOD:                                                    (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                 Leu"                                                                           (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 46                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Asn-OH or                                        Asn-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                      (C) JOURNAL:                                                                  (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                       GluXaaGlnLeuMetHisAsnLeuG lyLysSerIleGlnAspLeu                                 151015                                                                         ArgArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThr                                  202530                                                                         AlaG luIleArgAlaThrSerGluValSerProAsnSerLysPro                                 354045                                                                         Xaa                                                                            (2) INFORMATION FOR SEQ ID NO:18:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 32 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                  (I) ORGANELLE:                                                                (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 3                                                                (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                 Leu"                                                                           (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 32                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ala-OH or                                        Ala-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                    (D) VOLUME:                                                                   (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                       SerGluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGln Asp                                 151015                                                                         LeuArgArgArgPhePheLeuHisHisLeuIleAlaGluIleHis                                  202530                                                                         ThrXaa                                                                         (2) INFORMATION FOR SEQ ID NO:19:                                               (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                         (D) DEVELOPMENTAL STAGE:                                                      (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                      (ix) FEATURE:                                                                 (A) NAME/KEY: modified-site                                                    (B) LOCATION: 3                                                                (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                 Leu"                                                                           (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 36                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ala-OH or                                         Ala-NH2"                                                                      (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                       SerGluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAsp                                  151015                                                                         LeuArgArgArgPhePheLeuHisHisLeuIleAlaGluIleH is                                 202530                                                                         ThrAlaGluIleArgXaa                                                             35                                                                             (2) INFORMATION FOR SEQ ID NO:20:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 40 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                             (iv) ANTI-SENSE:                                                              (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY:                                                                  (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                        (B) MAP POSITION:                                                              (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 3                                                                (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                 Leu"                                                                            (ix) FEATURE:                                                                 (A) NAME/KEY: modified-site                                                    (B) LOCATION: 40                                                               (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Val-OH or                                        Val-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                      (F) PAGES:                                                                    (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                               (J) PUBLICATION DATE:                                                          (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                       SerGluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAsp                                  15 1015                                                                        LeuArgArgArgPhePheLeuHisHisLeuIleAlaGluIleHis                                  202530                                                                         ThrAlaGluIleArgAlaThrSerGluXaa                                                 35 40                                                                          (2) INFORMATION FOR SEQ ID NO:21:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 47 amino acid residues                                             (B) TYPE: amino acid                                                           (C) STRANDEDNESS: single                                                       (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE:                                                            (iii) HYPOTHETICAL:                                                            (iv) ANTI-SENSE:                                                               (v) FRAGMENT TYPE:                                                             (vi) ORIGINAL SOURCE:                                                          (A) ORGANISM:                                                                  (B) STRAIN:                                                                    (C) INDIVIDUAL ISOLATE:                                                        (D) DEVELOPMENTAL STAGE:                                                       (E) HAPLOTYPE:                                                                 (F) TISSUE TYPE:                                                               (G) CELL TYPE:                                                                 (H) CELL LINE:                                                                 (I) ORGANELLE:                                                                 (vii) IMMEDIATE SOURCE:                                                        (A) LIBRARY:                                                                   (B) CLONE:                                                                     (viii) POSITION IN GENOME:                                                     (A) CHROMOSOME/SEGMENT:                                                         (B) MAP POSITION:                                                             (C) UNITS:                                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 3                                                                (C) IDENTIFICATION METHOD:                                                     (D) OTHER INFORMATION: /note="Ile, Thr, Val or                                 Leu"                                                                           (ix) FEATURE:                                                                  (A) NAME/KEY: modified-site                                                    (B) LOCATION: 47                                                               (C) IDENTIFICATION METHOD:                                                      (D) OTHER INFORMATION: /note="Asn-OH or                                       Asn-NH2"                                                                       (x) PUBLICATION INFORMATION:                                                   (A) AUTHORS:                                                                   (B) TITLE:                                                                     (C) JOURNAL:                                                                   (D) VOLUME:                                                                    (E) ISSUE:                                                                     (F) PAGES:                                                                     (G) DATE:                                                                      (H) DOCUMENT NUMBER:                                                           (I) FILING DATE:                                                                (J) PUBLICATION DATE:                                                         (K) RELEVANT RESIDUES IN SEQ ID NO:                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                       SerGluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAsp                                  151015                                                                         LeuArgArgArgPhePheLeuH isHisLeuIleAlaGluIleHis                                 202530                                                                         ThrAlaGluIleArgAlaThrSerGluValSerProAsnSerLys                                  354045                                                                         ProXaa                                                                     

What is claimed is:
 1. Peptides consisting of 28-32 amino acid residues and comprising the following peptide sequence:

    X-Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-His-Thr-Ala                     (I)

wherein X represents H, H-Gln, H-A-Gln-, H-Glu-A-Gln, or Ser-Glu-A-Gln-, wherein A is Ile, Thr, Val, or Leu, and amides and salts thereof. 